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Section I. Fungi and Sick Building Syndrome
Fungi and the Indoor Environment: Their Impact
on Human Health
J. D. COOLEY,* W. C. WONG,* C. A. JUMPER,y
AND D. C. STRAUS*
*Department of Microbiology and Immunology, Texas Tech University
Health Sciences Center, Lubbock, Texas 79430
y
I.
II.
III.
IV.
V.
VI.
VII.
VIII.
IX.
Department of Internal Medicine, Texas Tech University
Health Sciences Center, Lubbock, Texas, 79430
Introduction
Inhalation of Fungal Spores Causes Respiratory Disease in Humans
Correlation Between the Presence of Certain Fungi and SBS
Development of an Animal Model for Allergic Penicilliosis
Induced by the Intranasal Instillation of Viable Penicillium
chrysogenum Conidia
Cellular and Humoral Responses in an Animal Model
Inhaling Penicillium chrysogenum
Continually Measured Fungal Profiles in SBS
Evaluation of Fungal Growth on Cellulose-Containing and
Inorganic Ceiling Tile
The Presence of Fungi Associated with SBS in North American
Zoological Institutions
The Role (?) of Mycotoxins in SBS
References
3
5
9
13
16
19
22
23
24
27
I. Introduction
‘‘Yeast, molds, mushrooms, mildews, and the other fungi pervade
our world. They work great good and terrible evil. Upon them, indeed,
hangs the balance of life; for without their presence in the cycle of
decay and regeneration, neither man nor any other living thing could
survive’’ (Kavaler, 1965).
One of the most common questions asked concerning the seemingly
recent phenomenon of sick building syndrome (SBS) and fungal involvement is, ‘‘Is this a new thing and why haven’t I heard of it
before?’’ Man’s realization that mold growth in his buildings is a
bad thing began over 3300 years ago in the time of Moses. Leviticus
14:33–45 (the Old Testament) describes this quite well. ‘‘If the mildew
reappears in the house after the stones have been torn out and the
house scraped and plastered, the priest is to go and examine it and, if
the mildew has spread in the house, it is a destructive mildew;
the house is unclean. It must be torn down—its stones, timbers and
all the plaster—and taken out of the town to an unclean place.’’ What is
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ADVANCES IN APPLIED MICROBIOLOGY, VOLUME 55
Copyright 2004, Elsevier Inc.
All rights reserved.
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J. D. COOLEY et al.
truly amazing is that this course of action is not too different from what
we do today, over 33 centuries later. The building material used at that
time was ‘‘straw’’ bricks, that is, cellulose-based stones and plaster.
What of course is different today is that we now know what microorganisms cause these problems and we know, or at least strongly
suspect, what products these fungi produce that can cause health
problems in human beings.
One of the early scientific papers published regarding the effects of
mold spores on humans appeared in 1873 (Blackley). Charles Blackley,
who was one of the early describers of pollen skin tests, wrote about his
asthmatic responses to the inhalation of Penicillium species conidia
(spores) (Licorish et al., 1985). It now appears that the literature is quite
clear on the importance of the inhalation of fungal spores on respiratory disease in man. The Centers for Disease Control (CDC) recently
published a statement for the record for the United States House of
Representatives (Redd, 2002). In it they state, ‘‘While there remain
many unresolved scientific questions, we do know that exposure to
high levels of mold causes some illnesses in susceptible people. Because molds can be harmful, it is important to maintain buildings,
prevent water damage and mold growth, and clean up moldy materials.’’ We have spent the last decade trying to understand the above
concepts. It is our humble hope that some of the work we have done
can help elucidate the role of fungi in the phenomenon known as sick
building syndrome.
Reports in the literature about building structures with poor
indoor air quality (IAQ) increasingly appeared soon after the mid1970s (Hodgson, 1992; Spangler and Sexton, 1983). SBS, a term
that is sometimes used for symptoms commonly associated with poor
IAQ, was first described in 1982. The first study examining more than
one building with SBS was published in 1984 (Finnigan et al.).
Although SBS has been difficult to define, evidence is now coming
to the fore that seems to indicate the importance of indoor fungal
growth in this phenomenon (Straus, 2001). SBS literally means
that there is something inside of said building that is actually
making people sick. These symptoms most commonly are fatigue,
runny nose, itchy eyes, sore throat, and headaches (Cooley et al.,
1998). Although no single cause for the above symptoms is likely
to be found, the presence of certain molds is becoming increasingly
associated with this phenomenon (Burrell, 1991; Cooley et al., 1998;
Dales et al., 1991; Jaakkola et al., 2002; Lehrer et al., 1983; Miller,
1992).
FUNGI AND THE INDOOR ENVIRONMENT
5
II. Inhalation of Fungal Spores Causes Respiratory Disease in Humans
Our first study examining the role of fungi in SBS was published in
1998 (Cooley et al.). In that paper we showed that there was a correlation
between certain fungi (Penicillium species [Figs. 1 and 2, see color insert] in the air and Stachybotrys species [Figs. 3 and 4, see color insert]
on building surfaces) and the symptoms seen in SBS. The finding that
the elevation of culturable (viable) Penicillium species conidia in the
indoor air over those levels in the outside air caused health problems in
human beings should not have been a surprise. As mentioned previously, the inhalation of Penicillium species conidia was associated with the
initiation of an asthmatic attack as early as 1873 (Blackley). Alternaria
species spores and Penicillium species conidia were shown to provoke
immediate and delayed-type asthma in individuals already sensitized
to these organisms (Licorish et al., 1985). A 1998 study (Garret et al.)
demonstrated that childhood asthma could be correlated with exposure to Penicillium species conidia levels in the air but not to visible
mold. In many of our investigations, we observed that Penicillium
FIG. 1. Penicillium chrysogenum colonies on PDA for 7 days.
6
J. D. COOLEY et al.
FIG. 2. Penicillium chrysogenum at 400 magnification.
species tended to colonize the heating, ventilation, and air conditioning (HVAC) systems of buildings (Cooley and Wong, unpublished data
from ARAL database, 2003). In 2002, Gent et al., showed that infants
with high risk for development of asthma who were exposed to high
levels of Penicillium species conidia were at significant risk for persistent cough and wheeze. This study was particularly interesting, because this correlation between respiratory distress and mold exposure
was valid for Penicillium species conidia but not for Cladosporium
species spores. Obviously there is something different about the genus
Penicillium that sets it apart from other fungal genera in this regard. In
1984, Fergussen et al. described for the first time Penicillium species
allergic alveolitis caused by the faulty installation of a central heating
system unit that introduced a great deal of water into a residence. In
this case the two fungal species found growing in the dwelling were
FUNGI AND THE INDOOR ENVIRONMENT
7
FIG. 3. Stachybotrys chartarum colonies on PDA for 14 days.
P. chrysogenum and P. cyclopium. Finally, there is one other important
respiratory disease caused by the inhalation of Penicillium species
conidia. This disease is called cheese worker’s lung or cheese washer’s
disease (Straus, 2002). This is an occupational disease that can occur in
individuals who work in the cheese industry. Occupational lung diseases become more common as the world becomes more industrialized.
Some of the other more common occupational lung diseases include
maltster’s lung, farmer’s lung, bagassosis, suberosis, and wood pulp
worker’s lung. The organisms that cause the above diseases are Aspergillus clavatus, thermophilic actinomycetes, Penicillium frequentans,
and Alternaria species, respectively (Straus, 2002). These diseases are
all phenomena related to hypersensitivity pneumonitis (HP). HP is an
allergic reaction to a wide variety of different inhaled antigens. In the
case of cheese washer’s disease, the inhaled antigen is a fungus (either
Penicillium casei or Penicillium roqueforti, which are used to flavor the
cheese). The first report of cheese washer’s disease was in Germany in
1969 (DeWeck et al.). In this study, two individuals reported difficulty
8
J. D. COOLEY et al.
FIG. 4. Stachybotrys chartarum at 400 magnification.
in breathing, fever, fatigue, and productive cough. These individuals
were cheese washers, and their symptoms appeared to be job related.
Because Penicillium species are grown on the surface of cheese as it is
being produced, it is necessary to have employees remove the fungi.
These individuals are, of course, called cheese washers. Cheese washing is performed by rubbing a course salt on the formed product and
then scrubbing it with a damp cloth (Marcer et al., 1996). The cheese
product itself supplies all the food and water that the fungi need to
multiply. Naturally, during this scrubbing process large numbers of
fungal conidia are emitted into the air surrounding the cheese product.
The organism most commonly found growing on the cheese in those
situations is P. casei (Schleuter, 1993). As expected, antibodies to
P. casei were detected in the sera of the two individuals described in
the above 1969 study (DeWeck et al.). Fortunately, the disease appears to
FUNGI AND THE INDOOR ENVIRONMENT
9
be reversible when the individual is no longer inhaling P. casei conidia
(DeWeck et al., 1969). However, if one is continually inhaling the same
type of fungal spores, ‘‘progressive pulmonary fibrosis’’ can occur with
resultant granulomatous tissue formation and subsequent shortness of
breath (Sell, 1996). Cheese washer’s disease was originally described in
Europe by DeWeck et al. (1969), but it has also been reported in the
United States. Campbell et al. (1983) examined a worker who developed
extrinsic allergic alveolitis (another term for hypersensitivity pneumonitis) caused by her inhalation of a fungus that was used in the production of the cheese and not one that grew on the cheese wheel as was
described by DeWeck et al. (1969). In this case, the cheese worker was
involved in the processing of blue cheese, which employs P. roqueforti.
Her job involved the breaking up of the blue cheese so it could be more
easily put in salad dressing bottles. This activity, of course, dispersed
high concentrations of P. roqueforti conidia into the air in her immediate vicinity. Antibodies to P. roqueforti were found in her serum
and lung washes (Campbell et al., 1983). There have been other reports
in the literature describing similar cases of cheese washer’s disease
(Guglielminetti et al., 2001; Marcer et al., 1996).
III. Correlation Between the Presence of Certain Fungi and SBS
In the 1998 study (Cooley et al.), we showed that there is a correlation between the presence of certain fungi in a building and the symptoms associated with SBS. The symptoms associated with SBS and
described in this study can be seen in Table I. In Table I, allergic-like
symptoms were the main complaint at all of the schools, and with the
moderate to high counts of culturable Penicillium species conidia
found in the complaint areas, this is not surprising. However, with
the exception of nausea, numerous symptoms other than allergic-like
were reported at each school. This implies that there may be other
mechanisms that may be inducing adverse health effects. In fact, we
always observed a variety of different visible fungal growth on surfaces
in the schools. This 22-month study of 48 schools in the southern
United States examined buildings in which there were concerns about
poor IAQ and health. Surface samples and indoor air and outdoor
culturable air samples were taken at all 48 buildings to look for visible
fungal growth as well as culturable airborne fungal spores. Five fungal
genera were usually found in the outdoor air. They were Cladosporium
(81.5%), Penicillium (5.2%), Chrysosporium (4.9%), Alternaria (2.8%),
and Aspergillus (1.1%). Cladosporium species are commonly the
dominant fungal species in the outdoor air (Shelton et al., 2002).
TABLE I
INCIDENCES PER 100 EMPLOYEES (95% Cl) OF REPORTED COMPLAINTS AND SYMPTOMS REGARDING INDOOR AIR QUALITY (IAQ)
UNITED STATES SCHOOLS BETWEEN 1994 AND 1996
Type of symptom
Incidence 95% Cl
Phenomenon
Incidence 95% Cl
Nasal drainage and
congestion
19.8
1.3
Discomfort
complaints
Itchy or watering eyes
14.3
1.1
Odors
5.2
Phenomenon
AT
48
Incidence 95% Cl
When are symptoms
the worst?
0.4
High humidity
12.0
0.9
5.6
1.2
Temperature (hot/cold)
7.2
0.1
Low humidity
0.0
0.0
Headaches
12.5
0.6
Noise
0.8
0.3
Spring
3.9
0.8
Sinus
10.3
0.5
Ventilation
6.1
0.3
3.4
0.4
14.3
1.0
Onset of symptoms
Cough
6.5
0.6
Entering the building
Shortness of breath
5.9
0.4
Sneezing
6.8
1.0
Contact problems
Severe sinus
Increased airway
infections
Summer
0.0
0.0
Fall
2.7
0.6
Winter
4.5
0.5
3.4
0.9
Start of School
5.7
2.0
Working in the
building
11.0
1.7
Morning
3.4
0.4
Start of school
11.3
1.9
Afternoon
1.1
0.3
Monday
0.8
0.3
Late in week
0.8
0.3
Dizziness
2.2
0.5
Fatigue
1.1
0.3
Flu-like symptoms
1.8
0.6
Never
3.5
0.8
No pattern
1.1
0.3
Nausea
1.8
3.4
Leave work
2.1
0.6
Always
2.3
0.6
31.3
6.8
2.5
1.1
When do symptoms
go away?
Allergies
17.0
1.0
Weekends
4.3
0.9
Before remedy
Asthma
1.4
0.3
Vacations
14.7
2.5
IAQ complaints
or symptoms
Other health conditions
1.2
0.5
Medications
4.4
0.2
After remedy
IAQ complaints
or symptoms
FUNGI AND THE INDOOR ENVIRONMENT
11
Visible surface fungal growth was observed at all 48 schools. At 20 of
the 48 schools studied, there were significantly (P < 0.0001) more
colony forming units per cubic meter of air (CFU/m3) of culturable
Penicillium species conidia in the air samples from complaint areas
as compared with the outside air samples and the indoor air samples
from noncomplaint areas (Figs. 5 and 6). At 5 of the 48 schools, there
were more (P ¼ 0.10) Penicillium species conidia in the air samples
from complaint areas when compared with the outdoor air samples and
the indoor air samples from noncomplaint areas were similar to those
in the outdoor air. However, in 11 of these schools, Stachybotrys atra
(aka chartarum) was isolated from building surfaces. Although visible
surface fungal growth was observed in the remaining 11 schools, the
culturable fungal air profiles were not significantly different between
the complaint and noncomplaint areas.
When the various schools took remedial action that resulted in an
indoor fungal profile that was similar to that observed outdoors and no
visible fungal growth was observed, the complaint profile dropped
FIG. 5. Bar graph of all air samples taken at the 48 schools.
12
J. D. COOLEY et al.
FIG. 6. Bar graph of all air samples taken at the 20 schools where Penicillium species
were the dominant fungi.
from 31.3% to 2.5%, which was a significant (P < 0.001) decrease
(Table I). However, from our experience over the last decade, if the
building is not properly maintained, with moisture events remediated
within 72 hours, these buildings can rapidly become microbially
contaminated.
Three basic strategies should be followed to maintain building performance and prevent microbial contamination: (a) routine surveillance inspections and prompt response to problems, (b) adequate
preventive maintenance of the building structure as well as HVAC
and plumbing systems, and (c) adequate housekeeping including an
emphasis on proper and routine cleaning (Shaughnessy and Morey,
1999).
FUNGI AND THE INDOOR ENVIRONMENT
13
IV. Development of an Animal Model for Allergic Penicilliosis Induced by
the Intranasal Instillation of Viable Penicillium chrysogenum Conidia
In an effort to try to determine why the inhalation of Penicillium
species conidia could produce the symptoms associated with SBS,
we developed an animal model for allergic penicilliosis induced
by the intranasal instillation of viable (culturable) P. chrysogenum
conidia (Cooley et al., 2000). Once we were able to singly disperse
the P. chrysogenum’s conidia, we determined that there were only
approximately 25% of the conidia that were actually viable—that is,
capable of reproducing. Since we could not readily determine the
difference between a viable conidium and a non-viable conidium, we
rendered one group of conidia totally non-viable. Therefore we could
assume that any difference between the two groups could be contributed to the viability of the conidia. In this study, C57 black/6 mice were
inoculated intranasally (IN) with 104 viable (V) and non-viable (NV)
P. chrysogenum for 6 weeks. This study showed that mice inoculated
IN for 6 weeks with 104 V PC (average viability 25%) produced
significantly more IgE (total serum), peripheral eosinophils, and airway
eosinophils (Figs. 7 and 8). Except for airway neutrophilia, mice
FIG. 7. Serum levels of IgG2a (solid bars) and total IgE (shaded bars) in mice inoculated
intranasally with viable and non-viable Penicillium chrysogenum conidia once a week for 6
weeks. *P < 0.05 compared with controls. Error bars represent standard error of means (SEM).
14
J. D. COOLEY et al.
FIG. 8. BAL fluid levels of eosinophils (solid bars) and IL-5 (shaded bars) in mice
inoculated intranasally with viable and non-viable Penicillium chrysogenum conidia
once a week for 6 weeks. *P < 0.05 compared with controls. Error bars represent standard
error of means (SEM).
receiving 104 NV P. chrysogenum IN did not demonstrate significant
increases in IgE (total serum), peripheral, or airway eosinophils (Fig. 7
and 8). However, the NV P. chrysogenum IN 104 group showed a
significant increase in total serum IgG2a and bronchoalveolar lavage
(BAL) fluid levels of interferon (IFN)-. Additionally, BAL from mice
inoculated IN with 104 V P. chrysogenum conidia demonstrated significant increases in the levels of interleukin (IL)-4 and IL-5 (Fig. 9). The
IgG2a/IgE ratio and the IFN-/IL-4 ratio were found to be lower in the
mice inoculated IN with 104 V P. chrysogenum conidia than in those
inoculated with 104 NV P. chrysogenum conidia and the control mice.
This suggests that the inflammatory response observed in the V P.
chrysogenum group was type 2 T helper cell (Th2) mediated. This
concept was supported by the demonstration that proteins extracted
from P. chrysogenum conidia incubated with serum from the V P.
chrysogenum inoculated conidia mice were IgE-specific, while the
serum from the NV P. chrysogenum group was not (Fig. 10). In this
paper we also clearly demonstrated that P. chrysogenum conidia are
easily phagocytized by mouse alveolar macrophages and degraded
FUNGI AND THE INDOOR ENVIRONMENT
15
FIG. 9. BAL fluid levels of IL-4 (solid bars) and IFN- (shaded bars) in mice inoculated
intranasally with viable and non-viable Penicillium chrysogenum conidia once a week
for 6 weeks. *P < 0.05 compared with controls. Error bars represent standard error of
means (SEM).
(Fig. 11). This study showed that the long-term (6-week) inhalation of V
P. chrysogenum conidia induced type 2 helper cell mediated inflammatory responses such as increases in total and conidia-specific serum
IgG1 and IgE. This was observed together with BAL fluid level increases
in IL-4 and IL-5, as well as airway and peripheral eosinophilia, both of
which are allergic reaction mediators.
Since the viable P. chrysogenum conidia are capable of reproducing,
these findings suggest that there is a difference between the viable
P. chrysogenum conidia and non-viable P. chrysogenum conidia. Many
researchers and clinicians in the past have been under the impression
that spores (conidia) are unlikely to release any antigens unless they
germinate, a process that requires several hours. This is because the
mucocilliary tract and the alveolar macrophages will remove most of
the fungal propagules prior to germination or attempted germination
(Platt-Mills et al., 1998).
16
J. D. COOLEY et al.
FIG. 10. Levels of conidia-specific IgG1 (shaded bars), IgE (white bars), and IgG2a (solid
bars) in pooled serum samples from mice inoculated intranasally with viable and nonviable Penicillium chrysogenum conidia once a week for 6 weeks. *P < 0.05 compared
with controls. Error bars represent standard error of means (SEM).
V. Cellular and Humoral Responses in an Animal Model
Inhaling Penicillium chrysogenum
We also examined the cellular and humoral responses in a mouse
model inhaling P. chrysogenum conidia (Cooley et al., 1999). The
retention of a particle is determined by the deposition and clearance
of the particle. The output of particles previously deposited in the
lungs is called clearance and refers to the process that physically
expels the particles from the lungs. This mechanism includes absorption, sneeze, cough, mucocilliary transport, and alveolar macrophage
clearance (Brain and Valberg, 1979). It should be kept in mind
that clearance is often of greater significance than deposition. Therefore, clearance efficiency may be the determining factor for total
integrated exposure, and, consequently, the probability of a pathologic
or physiological response, especially when particles are viable conidia.
FUNGI AND THE INDOOR ENVIRONMENT
17
FIG. 11. Ultrastructure of alveolar macrophages taken from the BAL fluid of mice
(A) 3 hours, (B) 6 hours, and (C) 24 hours after instillation of viable conidia
(magnification 10,000). Phagocytosed conidia (arrows) at various stages of digestion
were commonly observed within phagosomes of the macrophage at all the times studied.
Temporal correlation of conidia destruction was not apparent as many macrophages
contained conidia in various stages of breakdown, even after 3 hours. Residual bodies
were present in cells at all times, typical of alveolar macrophages. (D) Ultrastructure of
Penicillium chrysogenum conidia (magnification 43,750) before instillation (spore coat
(sc) between the arrow heads and spore vacuoles (v)). This morphology is comparable to
the minimally damaged installed conidia captured in (C). The conidia in (A) and (B) are
apparently in later stages of destruction.
Continuous exposure to moderate to high levels of P. chrysogenum
conidia in a structure over a period of time will have an impact on
the clearance efficiency versus a one-time exposure. Fungi produce a
variety of secondary metabolites, including mycotoxins and fungal
volatile organic compounds (VOCs). Mycotoxins are harmful to animals and humans. In addition to mycotoxins, some VOCs produced by
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J. D. COOLEY et al.
FIG. 12. Female C57Bl/6 mice were inoculated IN with 1 106 Penicillium
chrysogenum spores (viability 26%), resulting in a dose of 2.6 105 CFU. At various
time periods after the acute inoculation, the mice were euthanized, the lungs and
tracheas aseptically removed, homogenized, and serial dilutions plated on SDA plates
to determine percent spore viability. Each time period had a minimum of 6 mice. The -0indicates no viable spores were recovered. The error bars represent the standard error of
means (SEM).
actively growing fungi are known irritants or hazardous chemicals and
may pose a health risk to building occupants and have an impact on the
clearance efficiency of the lungs (Yang and Johanning, 1997).
In this study, viable P. chrysogenum conidia were recovered
from mouse lungs, as early as 15 minutes and 3 hours through 36
hours after IN inoculation of 106 conidia (26% viability) (Fig. 12). We
demonstrated that approximately 18% of the viable conidia were
actually deposited in the mouse lungs. However, by 12 hours postinoculation, only 104 viable conidia were detected. These data suggest
that the mucocilliary tract had cleared most of the inoculated
conidia, but 4% of the viable conidia were housed in the airways,
probably in the alveolar spaces, where they remained viable for up to
36 hours.
FUNGI AND THE INDOOR ENVIRONMENT
19
One 106 doses of viable P. chrysogenum conidia induced significant (P < 0.001) increases in tumor necrosis factor- (TNF-), while NV
P. chrysogenum conidia did not. When 1 104 doses (repeated for 3
weeks) of viable P. chrysogenum conidia were inoculated IN into mice
(C57 Black/6), significant (P < 0.05) increases in total serum IgE and
BAL IL-4 were observed, whereas this did not occur in mice receiving
1 104 NV P. chrysogenum conidia. These data also suggest that viable
P. chrysogenum conidia are capable of inducing an allergic response.
Moisture will stimulate viable P. chrysogenum conidia to attempt to
germinate. If there is a sufficient nutrient source, the conidia (spores)
will form germ tubes and hyphae and colonization will initiate. Although there is enough moisture in the lungs to stimulate germination
of P. chrysogenum conidia, the temperature (37 C) and the lack
of nutrients would inhibit the formation of a germ tube (Yang and
Johanning, 1997). However, observing viable P. chrysogenum conidia
in the lungs 36 hours after instillation certainly allows enough time for
attempted germination and the production of potential antigens. In
fact, we have been able to demonstrate that the viable P. chrysogenum
conidia are capable of producing such antigens (Schwab et al., 2003).
VI. Continually Measured Fungal Profiles in SBS
In a 1999 study (McGrath et al.), we sought to answer two questions.
The first was, ‘‘when taking a culturable indoor air sample, is that
sample an accurate reflection of the air in that building or is it just a
snapshot that changes immediately after the picture is taken?’’ The
second question was ‘‘do ‘sick’ or contaminated buildings stay or
remain contaminated over an extended period of time or do they get
better and then become contaminated again?’’ To answer these questions, we compared culturable fungal air profiles measured continually
over 6 hours in a documented ‘‘sick’’ building. We measured culturable
indoor air (IDA) samples in a room experiencing IAQ problems (heavily colonized with P. chrysogenum) with fungal profiles measured
concurrently in the culturable outdoor air (ODA) samples.
Investigators often use ODA samples as a baseline measurement in
which to compare what is found in the IDA samples. Indoor/outdoor
comparisons are commonly used to document the presence or infer the
absence of indoor, biologically derived contamination (Burge et al.,
1999). However, one should use caution and compare genera and
species and not genera only.
The dominant species collected in the IDA and ODA were Alternaria
species, Cladosporium species, and Penicillium species (Fig. 13). In the
20
J. D. COOLEY et al.
FIG. 13. Fungal concentrations measured in indoor and outdoor air. Values are mean
SEM. Each bar represents the average of all samples.
IDA, Penicillium species were consistently the dominant organisms,
ranging from 150 to 567 CFU/m3 (89.8–100% of the total viable fungi)
(Fig. 14). In the ODA, Cladosporium species were dominant in four of
the samples (40.0–70.6%), while Penicillium species were dominant
(52.7–79.6%) in two samples (Fig. 15). This study showed that as
expected, ODA fungal profiles are continually changing. Outdoor concentrations of some biological agents vary with time of day, wind
directions, relative humidity, and other factors. Depending on the
source of a biological agent, indoor air concentrations may be affected
by outdoor air ventilation rates, number of occupants or occupant
activity, and vibration and air movements within the structure
(Macher, 1999). The IDA fungal profiles in this particular ‘‘sick’’ building tended not to change, at least for the 6 hours we measured, which
was probably due to the very heavy colonization of Penicillium species
growing in the room. However, it has been our experience in sampling
hundreds of buildings that the IDA may only be a snapshot. If the IDA
is positive for increased fungal presence, as compared to the ODA, then
that suggests a strong indication of interior fungal growth. It should be
noted that failure to find a biological agent or related environmental
FUNGI AND THE INDOOR ENVIRONMENT
21
FIG. 14. Fungal profiles measured in indoor air. Values are mean SEM. Each bar
represents the mean of 3 samples.
FIG. 15. Fungal profiles measured in outdoor air. Values are mean SEM. Each bar
represents the mean of 3 samples.
22
J. D. COOLEY et al.
condition is not absolute assurance of their absence nor the absence of
exposure or risk.
Many investigators take only total spore trap sampling and usually do not take any or few culturable (viable) air sampling. The
Penicillium species and Aspergillus species conidia are single cell,
spherical in shape, 1 to 5 m in diameter, and are reported as Aspergillus/Penicillium-like spores. However, this can be very misleading in
that there are numerous genera of fungi that produce similar-looking
spores. With Penicillium species as one of the most common indoor
fungal colonizers, especially in the HVAC systems, the only way to
determine its presence is by culturable air sampling. Investigators can
never definitively conclude or prove that an environment is ‘‘safe’’ and
presents no risk of exposure to biological agents. In part, this means
that if the investigators have not looked for biological agents, they
cannot say that it is not there (Burge et al., 1999).
VII. Evaluation of Fungal Growth on Cellulose-Containing and
Inorganic Ceiling Tile
As we stated earlier in our introduction, mold has plagued mankind
since Moses. The construction materials used during biblical times
were ‘‘straw’’ bricks, cellulose-based stones, and plaster. As the standard of living has increased in the industrialized nations, the invention
of air conditioning, which led to increased productivity and laborsaving products, has also allowed the industrialized nations freedom
of architectural design, ignoring thousands of years of building experience. As the post–World War II building boom started, the industrialized nations changed the way buildings were constructed. Inorganic
plaster-covered walls were labor intensive and expensive. To reduce
the cost of construction and meet the burgeoning demand, the use of
gypsum board (1/200 to 3/400 gypsum covered with processed-paper
[cellulose-based] to maintain its rigidity) was begun. It is inexpensive
to manufacture and relatively labor free and rapid to install. A variety
of cellulose-based compounds could be used to texture and paint it or it
could be covered with wallpaper or vinyl paper. However, in the
process, we reverted back to the ‘‘straw’’ bricks, using processedcellulose substances that were ideal food sources for mold. The only
thing that was lacking to induce fungal growth was moisture.
The standard of living continued to increase and there was and still
is a great demand for gypsum board. When the energy crisis occurred
in 1972, we sealed up our buildings, closed our windows, and
recirculated our air so that we could reduce the soaring energy costs.
FUNGI AND THE INDOOR ENVIRONMENT
23
Because we knew that mold growth in buildings was due to water
intrusion, we thought that it was essentially impossible to keep water
out of buildings. This is due to the fact that many uncontrollable events
occur (e.g., roof leaks, water pipe breaks, and floods). When these
things happen, moisture is trapped in buildings, and combined with
poor preventive maintenance and ignorance, all of the ingredients are
in place to have mold problems associated with SBS. We thus decided
to see if it was possible to develop building materials that would not
support fungal growth, even after a significant water event. The objective of this study was to examine building materials that would not
support the growth of certain fungi after a wetting event, regardless of
whether an external food source was supplied (Karunasena et al.,
2000). The growth of three fungal genera (Stachybotrys, Penicillium,
and Cladosporium) was examined on inorganic ceiling tile (ICT) and
cellulose-containing ceiling tile (CCT) (Figs. 16 and 17). Both types of
ceiling tiles were wetted and inoculated with fungal spores of the
above three genera. The study showed that the ICT did not allow for
fungal growth while the CCT did (Fig. 18). These data demonstrate that
it is possible to develop building materials that will not support fungal
growth, even after a significant water event.
VIII. The Presence of Fungi Associated with SBS in North American
Zoological Institutions
The last study we would like to discuss addressed the presence of
fungi associated with SBS in American zoos (Wilson and Straus, 2002).
One of the ideas that led to this study was a perception that it is often
difficult to get animals to breed in captivity, especially in zoos. We
wondered if chronic exposure to SBS-associated fungi could affect
breeding success or animal morbidity and/or mortality. We examined
a total of 110 sites from five zoos in the United States to determine
whether SBS-associated fungi could be isolated. We also investigated
whether the presence of said fungi could be correlated with adverse
breeding success and/or morbidity and mortality. Culturable air samples and surface samples were taken at the above zoos. High levels of
P. chrysogenum conidia were found in the air of 16 sites at all 5 zoos.
Five viable growth sites of Stachybotrys chartarum (atra) were found at
2 zoos. A number of other fungal species were recovered from all zoos.
A Fisher exact test analysis demonstrated a nonrandom, significant
(P < 0.001) relationship between sites with a record of poor animal
health and high levels of airborne P. chrysogenum conidia. This study
suggests that significant numbers of airborne fungi associated with SBS
24
J. D. COOLEY et al.
FIG. 16. Colony-forming units of three different fungal genera on cellulose-containing
ceiling tile (CCT) and inorganic ceiling tile (ICT) exposed to fungal conidia and
incubated for 7 days. Horizontal bars represent original conidia concentrations. Error
bars represent standard deviation. The single asterisk (*) indicates a significant increase
in the number of viable spores harvested from the tiles compared to the original inocula,
and the double asterisk (**) indicates a significant decrease in the number of viable
spores harvested from the tiles compared to the original inocula. A Mann-Whitney rank
sum test was utilized (P < 0.05) to compare the inocula to the conidia harvested from the
tiles. Clado signifies Cladosporium cladosporioides, Pen signifies Penicillium chrysogenum, and Stach signifies Stachybotrys chartarum.
are in North American zoological institutions, and therefore zookeepers
need to be aware of them and the potential problems they can cause.
IX. The Role (?) of Mycotoxins in SBS
Finally, we would like to briefly discuss the role of mycotoxin production by fungi in the role of SBS. There is little doubt that mycotoxins are produced by fungi inside buildings in which the organisms are
growing. This has been shown by a number of investigators (Croft et al.,
1986; Engelhart et al., 2002; Kielsen et al., 1999; Nieminen et al., 2002;
Nikulin et al., 1994; Tuomi et al., 2000). We know that there are
FUNGI AND THE INDOOR ENVIRONMENT
25
FIG. 17. Colony-forming units of three different fungal genera on CCT and ICT with
400 l of TSB exposed to fungal conidia and incubated for 7 days. Horizontal bars
represent original conidia concentrations. Error bars represent standard deviation. The
single asterisk (*) indicates a significant increase in the number of viable spores
harvested from the tiles compared to the original inocula, and the double asterisk (**)
indicates a significant decrease in the number of viable spores harvested from the tiles
compared to the original inocula. A Mann-Whitney rank sum test was utilized (P < 0.05)
to compare the inocula to the viable conidia harvested from the ceiling tiles. Clado
signifies Cladosporium cladosporioides, Pen signifies Penicillium chrysogenum, and
Stach signifies Stachybotrys chartarum.
trichothecene mycotoxins on the spores of Stachybotrys atra (Sorenson
et al., 1987) and that these spores can be taken into the human
lung (Elidemir et al., 1999). In many of our examinations of tape surface
samples, we observed Penicillium species growing with Stachybotrys
atra colonies (Cooley and Wong, unpublished data from ARAL database, 2003). Therefore the obvious conclusion one can draw from
this is that trichothecene mycotoxins can enter the lungs of human
beings in Stachybotrys-infested houses. There is some evidence that
implicates trichothecene mycotoxins in illnesses seen in Stachybotrysinfested buildings and/or houses (Croft et al., 1986; Elidemir et al.,
1999; Flappan et al., 1999; Hodgson et al., 1998; Smoragiewicz et al.,
1993). Indeed, Croft et al. (2002) recently demonstrated the presence of
26
J. D. COOLEY et al.
FIG. 18. Fungal growth on cellulose-containing ceiling tile (CCT) and inorganic ceiling
tile (ICT). CCT (B, C) and ICT (E, F) were inoculated with 3.0 104 CFU of S. chartarum
and incubated for 7 days at 25 C and 80% RH. A and D represent uninoculated CCT and
ICT, respectively. B and E represent CCT and ICT inoculated with 3.0 104 CFU of S.
chartarum plus 0 l of TSB, respectively. C and F represent CCT and ICT inoculated with
3.0 104 CFU of S. chartarum plus 400 l of TSB, respectively. These results are
representative of all of the fungi used in this study.
trichothecene mycotoxins in the urine of patients who had been exposed to these compounds in mold-contaminated buildings. We know
what kinds of symptoms trichothecene mycotoxins can produce in
human beings. Phase I clinical evaluation of anguidine (a simple
trichothecene produced by Fusarium equiseti) was administered by
rapid intravenous infusion daily to a number of patients to determine
its effectiveness as an anti-cancer drug (Goodwin et al., 1978; Murphy
et al., 1978). While this compound had little or no anti-tumor activity,
it was quite toxic at some of the dosages employed. Symptoms of
toxicity included nausea; vomiting; low blood pressure; central nervous system symptoms such as drowsiness, ataxia, and confusion;
diarrhea; fever and chills; burning erythema, inflammation of the mucous membranes of the mouth; difficulty in breathing; and moderate
myelosuppression. Higher doses showed an association with lifethreatening liver function impairment. While we can not yet say that
FUNGI AND THE INDOOR ENVIRONMENT
27
mycotoxin production in our buildings is definitely responsible for
some of the illnesses seen in those living or working in Stachybotrysinfested buildings, it is clear that exposure to these structures by
human beings is something to be avoided.
ACKNOWLEDGMENTS
The authors would like to thank the following for financial support: Assured IAQÕ,
Dallas; Texas Tech University Health Sciences Center; and the State of Texas Higher
Education Coordinating Board. We would also like to thank Enusha Karunasena, Trevor
Brasel, and Nancy Markham, and also Drs. Chris Schwab, Jim Hutson, Jim Williams,
Steve Wilson, and Jim McGrath, who helped generate the data reported here.
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Fungal Contamination as a Major Contributor to
Sick Building Syndrome
DE-WEI LI
AND
CHIN S. YANG
P & K Microbiology Services, Inc., 1936 Olney Ave
Cherry Hill, New Jersey 08003
I. Introduction
II. Effects of Indoor Fungi on Human Health
A. Fungal Allergies and Allergenic Respiratory Diseases
B. Infectious Diseases
C. Mycotoxins and Their Significance to Human Health
D. Volatile Organic Compounds (VOCs)
E. Glucans
III. Indoor Fungi
A. Fungal Identification
B. Airborne Fungi
C. Fungi Growing on Indoor/Building Materials
D. Fungal Biodiversity Indoors
E. Stachybotrys chartarum and Other Stachybotrys spp.
F. PCR and Molecular Techniques
IV. Ecological Factors of Fungi Indoors
A. Physical Factors
B. Building Characteristics
C. Succession and Changes in Indoor Fungi
V. Recent Studies on Limits/Exposures of Indoor Fungi
VI. Conclusions
References
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I. Introduction
Fungi are heterotrophic eukaryotes producing exoenzymes and absorbing their nutrients by a network of hyphae and reproducing
through development of spores. They belong to Kingdom Eumycota
(Kingdom of Fungi) or Kingdom Chromista (Kendrick, 2000). However,
there is one group of organisms, which are traditionally studied by
mycologists, called pseudofungi (such as slime molds in myxomycetes), that belong to Kingdom Protozoa (Kirk et al., 2001). Fungi are
a very large, diverse, and heterogeneous group of organisms found in
nearly every ecological niche (Alexopoulos et al., 1996). They play a
very important role in our ecosystem and our daily life. Fungi always
play dual roles on the earth: (a) a positive one as food, medicine, key
components in food processing, decomposers breaking down organic
matters to recycle the nutrients in the ecosystem and to form symbiotic
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Copyright 2004, Elsevier Inc.
All rights reserved.
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LI AND YANG
relationship with other organisms; (b) a negative one as pathogens to
humans, plants, and animals; as allergens, producing secondary metabolites, mycotoxins, fungal volatile organic compounds (VOCs); and as
glucans, which are detrimental to human health and building occupants (Batterman, 1995; Ezeonu et al., 1994; Miller, 1992, 1993). A large
number of fungi are saprophytes or decomposers, which mainly occur
in natural environments (outdoors) such as soil and plant debris. Some
of these fungi can be found in indoor environments. One key factor that
we should keep in mind is that most indoor fungi originate from the
outdoor environment. Certain indoor fungal contaminants pose a potential health risk to building occupants and may lead to sick building
syndrome (Gravesen et al., 1994; Miller, 1992, 1993; Samson et al.,
1994). Indoor fungi have attracted unprecedented attention because
of their potential health effects on humans in the last decade. Public
awareness of indoor fungi in return generates more research to elucidate their roles in indoor environments and human health. Indoor
fungus is not only a scientific issue but is also becoming a social issue.
Public awareness does not automatically mean a good understanding of
the indoor molds. There are still many key questions that need to be
answered to have a better understanding of the indoor mold issue.
This chapter reviews available literature on fungal contamination as
a major contributor to sick building syndrome.
II. Effects of Indoor Fungi on Human Health
A. FUNGAL ALLERGIES AND ALLERGENIC RESPIRATORY DISEASES
Allergy (Gk allos, other; ergon, work) is a disease or reaction caused
by an immunoglobin E (IgE)-mediated immune response to one or more
environmental agents, resulting in tissue inflammation and organ dysfunction, and an exaggerated and pathological variant of a normal
immune mechanism (Klein, 1990; Middleton, Jr. et al., 1988; Paul,
1989; Raven and Johnson, 1986). Fungal spores are a well known cause
of allergic diseases (Chapman, 1999; Gravesen, 1979; Horwitz and
Bush, 1997) and were identified as one of the major indoor allergens
(Burr, 1999; Pope et al., 1993; Ruotsalainen et al., 1995). Allergy is
common throughout the world. The prevalence of sensitivity to specific allergens is determined by both genetic predilection and geographic
and cultural factors responsible for exposure to the allergen (Stites and
Terr, 1991).
All fungi may be allergenic, depending on the individual, the
exposure situation, and the dose (Ruotsalainen et al., 1995). The genera
FUNGAL CONTAMINATION AS A MAJOR CONTRIBUTOR
33
of fungi, which have been reported to be allergenic, are compiled in
Table I. Since the late 1870s, when Blakeley developed symptoms of
bronchial asthma and ‘‘chest tightness’’ after inhaling spores from
Penicillium cultures, it has been believed that mold sensitization is
an important cause of respiratory allergy (Barth, 1981; Karlsson-Borgå,
1989; Salvaggio, 1986).
Allergy is perhaps the most common human reaction to airborne
fungal spores (including conidia). About 20% of the population are
allergic individuals with a genetic predisposition to produce IgE antibody to allergens that are either inhaled or ingested (Kaplan et al.,
1991; Tizard, 1988). The percentages of populations allergic to molds
vary from 2% to 18%, and around 80% of asthmatic patients are
allergic to molds (Flannigan et al., 1991). About 20% of the population
are atopic and easily sensitized by concentrations usually found in the
outdoor air spora (up to 106 spores/m3). These people react immediately on exposure in the upper airways with hay-fever-like symptoms or
asthma and may become sensitive to several of the allergens to which
they are exposed. The remainder of the population requires more
intensive exposure (106–109 spores/m3) for sensitization (Lacey, 1981).
The incidence and prevalence of allergic diseases is increasing
(Ruotsalainen et al., 1995). Allergies affect as many as 50 million
people in the United States, costing them up to $5 billion annually
(Jaroff, 1992), and the number is obviously much higher at present.
Asthma, rhinitis, hypersensitivity pneumonitis, and humidifier lung
are allergenic respiratory diseases that, to a certain degree, may be
related to exposure to airborne fungi.
Asthma is the most common chronic respiratory disease in all
countries. Both the severity and prevalence of persistent asthma appear to be increasing, leading to urgency in the search for its causes
(Woolcock, 1991). Four thousand people a year reportedly died from
allergic asthma attack in the United States (Jaroff, 1992). In Australia,
asthma mortality rates doubled from 1978 to 1988 (Young et al., 1991).
Immediate-type asthma symptoms were produced with both whole
spores and spore extracts of Alternaria and Penicillium (Licorish et al.,
1985; Salvaggio, 1986). Airborne fungal spores are ubiquitous (Howard,
1984) and are known in many cases to be allergenic, so it is not
surprising that mold spores are an important cause of asthma. At
present the relationship between mold spores and asthma is still poorly
understood. In Madison, Wisconsin, in a series of 100 consecutive
patients with allergic asthma, skin tests were uniformly positive to
Alternaria (Reed, 1985). Most of these patients had asthma symptoms
not only before and after the ragweed season (about August 10 to
34
LI AND YANG
TABLE I
FUNGAL GENERA REPORTED TO BE ASSOCIATED WITH ALLERGY
Fungus
Absidia
Order
Mucorales
Division
Zygomycota
Acremonium
Hyphomycetes
Acrogenospora
Hyphomycetes
Acrothecium
Hyphomycetes
Agaricus
Agaricales
Basidiomycotina
Agrocybe
Agaricales
Basidiomycotina
Alternaria
Hyphomycetes
Amanita
Agaricales
Basidiomycotina
Armillaria
Agaricales
Basidiomycotina
Arthrinium
Hyphomycetes
Aspergillus
Hyphomycetes
Aureobasidium
Hyphomycetes
Bispora
Hyphomycetes
Boletinellus
Boletales
Basidiomycotina
Boletus
Boletales
Basidiomycotina
Calvatia
Lycoperdales
Basidiomycotina
Candida
Yeast
Cantharellus
Aphyllophorales
Basidiomycotina
Chaetomium
Sordariales
Ascomycotina
Chlorophyllum
Agaricales
Basidiomycotina
Hypocreales
Ascomycotina
Botrytis
Hyphomycetes
Cladosporium
Claviceps
Hyphomycetes
Coniosporium
Hyphomycetes
Coprinus
Agaricales
Basidiomycotina
Coriolus
Aphyllophorales
Basidiomycotina
Cryptococcus
Hyphomycetes
Cryptostroma
Hyphomycetes
Cunninghamella
Mucorales
Zygomycota)
Dacrymyces
Dacrymycetales
Basidiomycotina
Daldinia
Xylariales
Ascomycotina
Debaryomyces
Saccharomycetales (Yeast)
Ascomycotina
Curvularia
Dicoccum (Trichocladium)
Hyphomycetes
Hyphomycetes
(continued)
35
FUNGAL CONTAMINATION AS A MAJOR CONTRIBUTOR
TABLE I (Continued )
Fungus
Didymella
Order
Dothideales
Division
Ascomycotina
Drechslera
Hyphomycetes
Epicoccum
Hyphomycetes
Epidermophyton
Hyphomycetes
Erysiphe
Erysiphales
Eurotium
Eurotiales
Ascomycotina
Fomes
Aphyllophorales
Basidiomycotina
Fuligo
Ascomycotina
Myxomycetes
Fusarium
Hyphomycetes
Ganoderma
Aphyllophorales
Basidiomycotina
Geastrum
Lycoperdales
Basidiomycotina
Geotrichum
Gibberella
Hyphomycetes
Hypocreales
Ascomycotina
Diaporthales
Ascomycotina
Gliocladium
Gnomonia
Hyphomycetes
Graphium
Hyphomycetes
Helminthosporium
Hyphomycetes
Hypholoma
Agaricales
Basidiomycotina
Inonotus
Aphyllophorales
Basidiomycotina
Leptosphaeria
Dothideales
Ascomycotina
Leptosphaerulina
Dothideales
Ascomycotina
Lycoperdon
Lycoperdales
Basidiomycotina
Malassezia
Hyphomycetes
Merulius (=Phlebia)
Microsphaera
Basidiomycotina
Erysiphales
Microsporum
Hyphomycetes
Monilia
Mucor
Ascomycotina
Hyphomycetes
Mucorales
Mycogone
Zygomycota
Hyphomycetes
Naematoloma
Agaricales
Basidiomycotina
Neurospora
Sordariales
Ascomycotina
Nigrospora
Hyphomycetes
Oidium
Hyphomycetes
Paecilomyces
Hyphomycetes
Papularia
Hyphomycetes
(continued)
36
LI AND YANG
TABLE I (Continued )
Fungus
Order
Penicillium
Division
Hyphomycetes
Phoma
Coelomycetes
Phycomyces
Mucorales
Zygomycota
Phytophthora
Peronosporales
Oomycota
Piptoporus
Aphyllophorales
Basidiomycotina
Pisolithus
Sclerodermatales
Basidiomycotina
Pleospora
Dothideales
Ascomycotina
Pleurotus
Aphyllophorales
Basidiomycotina
Podaxis
Podaxales
Basidiomycotina
Polyporus
Aphyllophorales
Basidiomycotina
Poria
Aphyllophorales
Basidiomycotina
Psilocybe
Agaricales
Basidiomycotina
Puccinia
Uredinales
Basidiomycotina
Rhizopus
Mucorales
Zygomycota
Rhodotorula
Yeast
Basidiomycotina
Saccharomyces
Endomycetales (Yeast)
Ascomycotina
Scleroderma
Sclerodermatales
Basidiomycotina
Serpula
Aphyllophorales
Basidiomycotina
Sphaerotheca
Erysiphales
Ascomycotina
Yeast
Basidiomycotina
Scopulariopsis
Hyphomycetes
Spondylocladium
Sporobolomyces
Hyphomycetes
Sporotrichum
Hyphomycetes
Stachybotrys
Hyphomycetes
Stemonitis
Myxomycetes
Stemphylium
Hyphomycetes
Stereum
Aphyllophorales
Basidiomycotina
Syncephalastrum
Mucorales
Zygomycota
Tetracoccosporium
Hyphomycetes
Thermomyces
Hyphomycetes
Tilletiopsis
Hyphomycetes
Tilletia
Basidiomycotina
Torula
Hyphomycetes
Trichoderma
Hyphomycetes
Trichophyton
Hyphomycetes
(continued)
37
FUNGAL CONTAMINATION AS A MAJOR CONTRIBUTOR
TABLE I (Continued )
Fungus
Order
Trichothecium
Typhula
Hyphomycetes
Aphyllophorales
Basidiomycotina
Ustilaginales
Basidiomycotina
Urocystis
Ustilago
Division
Basidiomycotina
Verticillium
Hyphomycetes
Wallemia
Hyphomycetes
Xylaria
Xylariales
Ascomycotina
Xylobolus
Aphyllophorales
Basidiomycotina
Chapman (1986); Ibanez et al. (1988); Latgé and Paris (1991); Santilli et al. (1990); Shen et al.
(1990); Smith (1990); Van Bronswijk et al. (1986).
September 20) but also during the time of year Alternaria spore counts
are high (July through October) (Reed, 1985). Cladosporium herbarum
has been shown to be a potential cause of allergic asthma and rhinitis
(Malling, 1990).
In a recent study, the prevalence of most building-related symptoms
was between 32% and 62%. Positive basophile histamine release
(HRT), showing serum IgE specific to one or more of the molds, was
observed in 37% of the individuals (Lander et al., 2001). The highest
frequency of positive HRT was found to Penicillium chrysogenum and
then to Aspergillus species, Cladosporium sphaerospermum, and Stachybotrys chartarum (Lander et al., 2001). Savilahti et al. (2000)
showed that moisture damage and exposure to molds increased the
indoor air problems of schools and affected the respiratory health of
children.
Cladosporium, Alternaria, Penicillium, Aspergillus, and Mucor were
reported to be the commonest allergenic fungi (Furuuchi and Baba,
1986; Malling et al., 1985). Cladosporium is believed to be the most
common one causing mold allergy (Malling et al., 1985). However, the
most prevalent airborne fungi are not necessarily the most potent
allergens, at least as determined by prick testing (Terracina and Rogers,
1982). Spores of Alternaria alternata and those of the closely related
genera Stemphylium and Ulocladium are considered to be the most
important mold allergens in the United States (Hoffman, 1984;
O’Hollaren et al., 1991; Reed, 1985). Penicillium exposure was a risk
factor for asthma, while Aspergillus exposure was a risk factor for atopy
(a genetic trait of increased allergen sensitivity) (Garrett et al., 1998).
38
LI AND YANG
Chow et al. (2000) characterized Pen n 13 as a major allergen of Penicillium notatum (a synonym of P. chrysogenum).
Aspergillus restrictus was demonstrated to be a potentially important
causative agent in atopic diseases when using skin prick tests and
radioallergosorbent test (RAST) on 24 patients (Sakamoto et al., 1990).
Aspergillus species and in particular Aspergillus fumigatus appeared to
be the etiological agents in various lung diseases and allergens. Inhalation of low doses of Aspergillus spores may induce sensitization and
asthma in sensitive patients, while inhalation of high doses may trigger
alveolitis and farmer’s lung (Wallenbeck et al., 1991). Martinez Ordaz
et al. (2002) of Mexico found that the association of skin reactivity and
indoor exposure was significant only for Aspergillus.
Curvularia lunata was found to be a cause of allergic bronchopulmonary disease (Halwig et al., 1985). Epicoccum nigrum was reported
to be able to colonize nasal sinuses and cause allergic fungal sinusitis
(Noble et al., 1997). Sooty molds caused allergies ranging from rhinitis
to asthma in the eastern United States (Santilli et al., 1985).
Ascospores are important airborne allergens and present unique
antigens (Eversmeyer and Kramer, 1987). Fifteen of 18 patients reportedly reacted to Leptosphaeria ascospores (Burge, 1986). About 40% of
atopic patients reacted to at least 1 ascomycete preparation. Chaetomium species, particularly C. globosum, are important ascomycetes
commonly found growing indoors on water-damaged paper and wood
products.
Basidiospores of Agaricus campestris, Coprinus micaceus, Lycoperdon perlatum, Scleroderma lycoperdoides, and Ustilago maydis
caused allergies ranging from rhinitis to asthma in the eastern United
States (Santilli et al., 1985). Basidiospores are antigenic and can elicit
immediate skin reactivity in sensitive patients. Mushrooms and basidiospores are considered most likely to be of outdoor origin, although
mycelia and conidia of wood decay fungi and, occasionally, mushrooms of the genus Coprinus and wood decay fungi have been identified in indoor environments with a chronic water-damage history.
In a military hospital building in Finland with severe, repeated, and
enduring water and mold damage, the most abundant species was
Sporobolomyces salmonicolor. Four new cases of asthma, confirmed
by S. salmonicolor inhalation provocation tests, were found among the
hospital personnel, one of whom was also found to have alveolitis
(Seuri et al., 2000). Seven other workers with newly diagnosed rhinitis
reacted positively in nasal S. salmonicolor provocation tests. Skin
prick tests of Sporobolomyces were negative among all 14 workers
(Seuri et al., 2000).
FUNGAL CONTAMINATION AS A MAJOR CONTRIBUTOR
39
Several epidemiologic studies concerning water damage, fungal
growth, and exposure to mold spores have been conducted in a number
of countries. The occurrence of Cladosporium, Aspergillus versicolor,
and Stachybotrys showed some value as an indicator of moisture damage. Presence of moisture damage in school buildings was a significant
risk factor for respiratory symptoms in school children (Meklin et al.,
2002). The association between moisture damage and respiratory
symptoms of children was significant for buildings of concrete/brick
construction but not for wooden school buildings. The highest symptom prevalence was found during spring seasons, after a long exposure
period in damaged schools (Meklin et al., 2002).
Questionnaire surveys conducted in the United Kingdom,
Canada, United States, and the Netherlands showed positive correlations between self-reported allergenic respiratory symptoms and
self-reported water damage and indoor fungi problems (Andrae et al.,
1988; Brunekreef, 1989; Dales et al., 1991a; Dekker et al., 1991; Melia
et al., 1982; Strachan, 1988; Strachan and Sanders, 1989; Strachan
et al., 1990; Waegemaekers et al., 1989). Most studies identified an
association between airborne fungal spore concentrations and selfreported allergic symptoms in the United Kingdom, Sweden, and the
Netherlands (Holmberg, 1987; Platt et al., 1989; Strachan et al., 1990;
Waegemaekers et al., 1989), but there is not always a correlation between indoor spore counts and symptoms found in research (Tobin
et al., 1987).
Yang et al. (1997) showed that the prevalence of respiratory symptoms was consistently higher in homes with dampness than in nondamp homes. Dampness in the home can be used as a strong predictor
of and a risk factor for respiratory symptoms and is a considerable
public health problem in Taiwan (Yang et al., 1997). A significant
relationship was found between dampness and work-related sick
building syndrome in day-care-center workers in Taiwan (Li et al.,
1997). A significant association was found between most buildingrelated symptoms (BRS) and positive basophil histamine release
(Lander et al., 2001). Jacob et al. (2002) found that mold spore counts
for Cladosporium and Aspergillus were associated with an increased
risk of allergic sensitization. Sensitized children exposed to high levels
of mold spores (>90th percentile) were more likely to suffer from
symptoms of rhinoconjunctivitis. Fungal allergies were more common
among children exposed to Cladosporium or Penicillium in winter or to
musty odor (Garrett et al., 1998).
In atopic children, total IgE showed a significant linear relation with
age. Prevalence of specific IgE for Cladosporium ranked first, followed
40
LI AND YANG
closely by Aspergillus and Alternaria (Nolles et al., 2001). Sensitization
to fungi is prevalent in childhood, with an age-dependent distribution
reaching maximum values at 7.7–7.8 years, followed by a decline for all
fungal sensitization with increasing age (Nolles et al., 2001).
Jaakkola et al. showed that the risk of asthma was related to the
presence of visible mold and/or mold odor in the workplace but not
to water damage or damp stains alone. The fraction of asthma attributable to workplace mold exposure was estimated to be 35.1% among the
exposed (Jaakkola et al., 2002). Large airborne fungal spore concentrations were recorded in association with musty odor, water intrusion,
high indoor humidity, limited ventilation through open windows, few
extractor fans, and failure to remove indoor mold growth in the homes
in the Latrobe Valley, Victoria, Australia (Garrett et al., 1998).
Aspergillus was associated strongly with work-related sick building
syndrome in day-care-center workers (Li et al., 1997). The diagnosis of
sick building syndrome related diseases, such as asthma, rhinitis, and
allergic alveolitis, can be very difficult. In the study of Thorn et al.
(1996) the symptoms of a school teacher, who was working in a school
that had indoor air quality problems on and off for several years, were
first interpreted as pulmonary embolism and later as atypical sarcoidosis. However, 6 years later the diagnosis of the illness was revised to
chronic allergic alveolitis.
It is important to understand that even correlations do not necessarily mean causal relations. Most studies on indoor airborne fungi were
conducted without taking allergic symptoms into account. Several
recent epidemiological studies have shown that long-duration indoor
exposure to certain fungi can result in hypersensitivity reaction and
chronic diseases. Mold spore levels comparable to outside background
levels are usually well tolerated by most people. Normal or ‘‘typical’’
indoor molds may vary depending on diurnal and seasonal patterns of
outdoor fungi, weather conditions, climate variations, and geographical
regions (Li and Kendrick, 1995a).
There are other diseases caused by airborne fungal allergens, such as
rhinitis, hypersensitivity pneumonitis, and humidifier lung (Burge,
1990b; Salvaggio, 1986). A number of occupational hypersensitivity
diseases of the lung can be implicated by fungi (Table II). Hypersensitivity pneumonitis, also called extrinsic allergic alveolitis, is a wellrecognized occupational disease. Hypersensitivity pneumonitis caused
by inhalation of spores from the edible mushroom Pholiota nameko
was documented by Nakazawa and Tochigi (1989). A diagnosis of
hypersensitivity pneumonitis caused by an Aspergillus species was
made by Jacobs et al. (1989). Pleurotus ostreatus was defined to be an
41
FUNGAL CONTAMINATION AS A MAJOR CONTRIBUTOR
TABLE II
FUNGI-IMPLICATED OCCUPATIONAL HYPERSENSITIVITY DISEASES OF THE LUNG
Fungal agent
Disease
Source
Alternaria sp.
Pulpmill worker’s lung
Aspergillus clavatus
Malt worker’s lung
Moldy pulpwood
Moldy malt
Aspergillus fumigatus
Wood trimmer’s disease
Moldy timber
Aspergillus sp.
Sawmill worker’s lung
Moldy
Aspergillus sp.
Woodchip handler’s disease
Moldy woodchip
Aureobasidium pullulans
Sauna taker’s lung
Sauna steam
Aureobasidium pullulans
Sequoiosis
Moldy sawdust
Botrytis cinerea
Vinegrower’s lung
Moldy fruit
Farnai rectivirgula
Potato riddler’s lung
Straw
Cryptostrama corticale
Maple bark disease
Moldy maple bark
Graphium sp.
Maple bark disease
Moldy maple bark
Micropolyspora faeni
Farmer’s lung
Moldy hay
Micropolyspora faeni
Mushroom worker’s lung
Mushroom compost
Micropolyspora faeni
Woodchip handler’s disease
Moldy woodchip
Mucor sp.
Woodchip handler’s disease
Moldy woodchip
Penicillium casei
Cheese worker’s lung
Cheese
Penicillium spp.
Suberosis, woodman’s disease
Cork
Rhizopus sp.
Wood trimmer’s disease
Moldy timber
Rhizopus (Mucor) stolonifer
Paprika worker’s lung
Moldy paprika
Serpula (Merulius) lacrymans
Dry rot lung
Moldy building
allergen by Horner et al. (1988). Extrinsic allergic alveolitis caused by
spores of Pleurotus ostreatus was reported by Cox et al. (1988).
In general, the adverse effects of fungal exposure by inhalation are
related to duration and intensity. Many studies have shown that ‘‘atypical’’ mold spore levels in the indoor environment increase because of
recurrent water leaks, home dampness, and high humidity, resulting in
increases of allergies and respiratory problems (Burge, 1990a,b; Dales
et al., 1991; Flannigan et al., 1991; Johanning et al., 1993; Rylander,
1994; Solomon et al., 1978; Strachan et al., 1990; Streifel and Rhame,
1993; Tripi et al., 2000). Path analysis showed that indoor total fungal
spores, indoor Aspergillus/Penicillium, and the age of the residences
had significant direct effects on allergic symptoms (Li, 1994).
There are still significant methodological problems in the preparation and production of reliable allergen extracts from fungi as
42
LI AND YANG
compared with those from cats, dust mites, and other better-characterized allergens. Extracts that are available correspond poorly with the
fungi often found in indoor surveys (Horner and Lehrer, 1999). One of
the technical difficulties is to produce enough spores for allergen
extraction. Common practice in fungal allergen extraction is to use a
mixture of spores and mycelia, which was believed to be a contributing
factor to inconsistency in the low sensitivity of fungal allergenic tests.
Because of the low sensitivity of some of the commercially available
mold allergen extracts, false-negative results are not uncommon. Patients with an atopy are frequently allergic to multiple fungal species
and manifest type I reactions (asthma, rhinitis, eczema, and hay fever).
One of the reasons for the poor correlations is reportedly that fungal
allergens are extracted from mostly vegetative hyphae grown in liquid
cultures, not from spores. The differences in allergencity between
hyphae and spores should be studied.
B. INFECTIOUS DISEASES
Fungi are mostly known to cause not only allergies but also infectious diseases to the skin and other body organs (Table III). Infections
caused by fungi are called mycoses. Mycoses are categorized into
endemic and opportunistic. Endemic mycosis is caused by the inhalation of airborne fungal spores found in certain geographic regions
where there is a higher frequency of such fungi because of unique soil
and flora (Lacey, 1991; Pitt, 1979). Opportunistic fungal pathogens
have a great public health importance, especially in immune system
compromised individuals such as those with human immunodeficiency virus (HIV) and organ transplants (Keller et al., 1999). These infections are not contagious, and the fungi are not obligatory pathogens.
Immunocompromised patients may be at an increased risk for opportunistic infections if opportunistic fungal pathogens become airborne
and their concentrations are significantly elevated in indoor air. The
major fungi causing mycosis and their medical significance are listed
in Table III.
Aspergillus fumigatus, A. flavus, and A. niger are among the fungi of
significant concern. Aspergillus fumigatus is the most important airborne pathogenic fungus (Brakhage and Langfelder, 2003) because of
its small respirable-size spores and its thermophilic nature (Klich and
Pitt, 1988). This is the very reason why A. fumigatus could cause a
significant problem in organ transplant wards in hospitals. Water damaged materials, houseplants, soil, bird and bat droppings, organic
waste, or other organic substrates in buildings may be a source of these
43
FUNGAL CONTAMINATION AS A MAJOR CONTRIBUTOR
TABLE III
PATHOGENIC FUNGI
Fungus
Absidia sp.
Classification
Disease
Affected area
Opportunistic
Systemic
mycosis
Zygomycosis
Face, sinuses,
(Mucormycosis,
gastrointestinal
phycomycosis)
tract, lungs
Cutaneous
mycosis
Keratomycosis
Subcutaneous
mycosis
Maduromycetoma
Opportunistic
Systemic
mycosis
Systemic
opportunistic
fungal disease
Lungs, deep tissue,
body organs, blood
Alternaria sp.
Opportunistic
Systemic
mycosis
Systemic
opportunistic
fungal disease
Lungs, deep tissue,
body organs, blood
Arthrographis sp.
Subcutaneous
mycosis
Dermatomycosis
Skin
Aspergillus
fumigatus
Opportunistic
Systemic
mycosis
Aspergillosis
Lung, skin,
mucocutaneous
tissue, any of the
body organs
Cutaneous
mycosis
Outer cutaneous
mycoses
Skin
Onychomycosis
Nails
Cunninghamelia
sp.
Mortierella sp.
Mucor sp.
Rhizopus sp.
Syncephalastrum sp.
Basidobolus ranarum
Rhizomucor sp.
Conidiobolus
coronatus
Acremonium sp.
Eye
Asp. flavus
Asp. niger
Asp. terreus
Asp. ustus
Aspergillus spp.
Aspergillus sp.
Otomycosis
Ear
Keratomycosis
Eye
(continued)
44
LI AND YANG
TABLE III (Continued )
Fungus
Classification
Disease
Systemic
opportunistic
fungal disease
Affected area
Aureobasidium
pullulans
Opportunistic
Systemic
mycosis
Lungs, deep tissue,
body organs, blood
Basidiobolus
sp.
Rare
Entomophthora
subcutaneous
basidiobolae
mycosis
Smooth skin
Beauveria
bassiana
Opportunistic
Systemic
mycosis
Systemic
opportunistic
fungal disease
Lungs, deep tissue,
body organs, blood
Blastomyces
dermatitidis
Systemic
mycosis
Blastomycosis
Primary infection in
lung, may spread to
all organs, skin
lesions are common
Candida
albicans
Cutaneous
mycosis
Intertriginous
candidosis
Moist skin areas: groin,
glans penis, scrotum,
folds of buttocks,
under the breast,
axilla, interdigital
spaces
Candida diaper
rash
Diaper area
Candidal
granuloma
Hands, feet, face, and
scalp
Candida
Nails and skin around
paronychia and
nail
onychomycosis
Mucocutaneoius
candidosis
Mucocutaneous areas
Thrush
Mouth and tongue
Perleche
Corners of mouth
Vaginal
candidosis
Vagina
Candida balinitis
Glans penis
Esophageal
candidosis
Esophagus
Perianal
candidosis
Anal ara
Chronic
mucocutaneous
candidosis
Candida albicans,
Candida spp.
Cutaneous
mycosis
Onychomycosis
Nails
(continued)
45
FUNGAL CONTAMINATION AS A MAJOR CONTRIBUTOR
TABLE III (Continued )
Fungus
Classification
Disease
Affected area
Opportunistic
Systemic
mycosis
Systemic
candidosis
Blood, heart tissue, kidney,
bladder, mucocutaneous
tissue (lungs are
colonized, but rarely
invaded)
Cutaneous
mycosis
Otomycosis
Ear
Candida sp.
Cutaneous
mycosis
Keratomycosis
Eye
Cercospora
apii
Opportunistic
Systemic
mycosis
Systemic
Opportunistic
fungal disease
Lungs, deep tissue,
body organs, blood
Chaetoconidium
sp.
Opportunistic
Systemic
mycosis
Systemic
Opportunistic
fungal disease
Lungs, deep tissue,
body organs, blood
Chrysosporium
parvum
Opportunistic
Systemic
mycosis
Systemic
Opportunistic
fungal disease
Lungs, deep tissue,
body organs, blood
Cladosporium
carrionii
Subcutaneous
mycosis
Chromomycosis
Skin surface, mostly
lower extremities
Cladosporium
trichoides
Opportunistic
Systemic
mycosis
Cerebral
Brain or central
chromomycosis
nervous system
Coccidioides
immitis
Systemic
mycosis
Coccidioidomycosis
Coprinus sp.
Miscellaneous
and rare
mycosis
Basidiomycosis
Cryptococcus
neoformans
Systemic
mycosis
Cryptococcosis
Lungs, central nervous
system, skin, any
organ of body
Curvularia
geniculata
Opportunistic
Systemic
mycosis
Systemic
Opportunistic
fungal disease
Lungs, deep tissue,
body organs, blood
Drechslera
hawaiiensis
Opportunistic
Systemic
mycosis
Entomophthora
(conidiobolus)
coronata
Rare
Entomophthorosubcutaneous
mycosis
mycosis
conididobolae
Nasal tissue and face
Primary infection in the
lung may spread to
other organs of the body;
skin lesion may be
produced
(continued)
46
LI AND YANG
TABLE III (Continued )
Fungus
Epidermophyton
floccosum
Classification
Cutaneous
mycosis
Disease
Affected area
Tinea cruris
Groin
Tinea pedis
Feet, interdigital
spaces, and soles
Tinea manuum
Palms and fingers
Tinea unguium
Nails
Epidermophyton
spp.
Cutaneous
mycosis
Dermatomycoses
Keratinized layers of
body: skin, hair,
nails
Exophiala
(Phialophora)
jeanselmei
Subcutaneous
mycosis
Phaeomycotic
Cyst
Smooth skin
Exophiala
(Phialophora)
spinifera
Subcutaneous
mycosis
Phaeomycotic
Cyst
Smooth skin
Exophiala
jeanselmei
Subcutaneous
mycosis
Maduromycetoma
Fonsecaea
compactum
Subcutaneous
mycosis
Chromomycosis
Fonsecaea
pedrosoi
Opportunistic
Systemic
mycosis
Cerebral
Brain or central
chromomycosis
nervous system
Fonsecaea
pedrosoi
Subcutaneous
mycosis
Chromomycosis
Skin surface, mostly
lower extremities
Fusarium sp.
Opportunistic
Systemic
mycosis
Fusarium sp.
Cutaneous
mycosis
Keratomycosis
Eye
Geotrichum
candidum
Opportunistic
Systemic
mycosis
Helminthosporium sp.
Opportunistic
Systemic
mycosis
Hendersonula
sp.
Subcutaneous
mycosis
Dermatomycosis
Skin
Histoplasma
capsulatum
Systemic
mycosis
Histoplasmosis
Primary infection
in lung
Skin surface, mostly
lower extremities
(continued)
47
FUNGAL CONTAMINATION AS A MAJOR CONTRIBUTOR
TABLE III (Continued )
Fungus
Classification
Disease
(H. duboisii in
Africa)
Affected area
Recticulorendothelial
system is invaded; bone
and kidney and other
organs, including the
skin, may be involved
Hortaea
(Phaeoannellomyces or
Exophiala)
werneckii
Superficial
mycosis
Tinea nigra
Thick stratum corneum,
palms, and feet
Loboa loboi
Rare
Lobomycosis
subcutaneous
mycosis
Malassezia
furfur
Superficial
infections
Pityriasis
versicolor
Microsporum
audouinii
Cutaneous
mycosis
Tinea capitis
Scalp
Cutaneous
mycosis
Tinea corporis
Smooth body skin
Cutaneous
mycosis
Tinea barbae
Beard and coarse body
hair
Tinea favosa
Scalp, skin, and nails
Dermatomycoses
Keratinized layers of
body: skin, hair, nails
Paracoccidioidomycosis
Subclinical infection
in lung, mucous
membranes, and
skin are involved
Smooth skin
M. canis
Microsporum spp.
Microsporum
canis
M. gypseum
Microsporum spp.
Microsporum
spp.
Microsporum
spp.
Cutaneous
mycosis
Paecilomyces sp.
Opportunistic
Systemic
mycosis
Paracoccidioides
brasiliensis
Systemic
mycosis
Penicillium sp.
Opportunistic
Systemic
mycosis
Pseudallescheria
(Allescheria or
Petriellidium),
boydii
Subcutaneous
mycosis
Maduromycetoma
(continued)
48
LI AND YANG
TABLE III (Continued )
Fungus
Phialophora
parasitica
Classification
Disease
Affected area
Opportunistic
Systemic
mycosis
Subcutaneous
mycosis
Phaeomycotic
Cyst
Smooth skin
Phialophora
repens
Subcutaneous
mycosis
Phaeomycotic
Cyst
Smooth skin
Phialophora
richardsiae
Subcutaneous
mycosis
Phaeomycotic
Cyst
Smooth skin
Phialophora
verrucosa
Subcutaneous
mycosis
Chromomycosis
Skin surface, mostly
lower extremities
Phoma
hibernica
Opportunistic
Systemic
mycosis
Phoma sp.
Subcutaneous
mycosis
Phaeomycotic
Cyst
Smooth skin
Piadraia hortae
Superficial
mycosis
Black piedra
Scalp and beard
Pityrosporum
orbiculare
Superficial
mycosis
Tinea
versicolor
Smooth body skin
Pseudallescheria
(Allescheria or
Petriellidium),
boydii
Opportunistic
Systemic
mycosis
Pythium
Miscellaneous
and rare
mycosis
Rhinosporidium
seeberi
Rare
Rhinosporidiosis
subcutaneous
mycosis
Schizophyllum
commune
Miscellaneous
and rare
mycosis
Scopulariopsis
brevicaulis
Opportunistic
Systemic
mycosis
Scopulariopsis sp.
Cutaneous
mycosis
Onychomycosis
Nails
Scytalidium sp.
Subcutaneous
mycosis
Dermatomycosis
Skin
Pythiosis
Nasal mucosa
Basidiomycosis
(continued)
FUNGAL CONTAMINATION AS A MAJOR CONTRIBUTOR
TABLE III (Continued )
Fungus
Classification
Sporothrix
schenckii
Subcutaneous
mycosis
Torulopsis
glabrata
Opportunistic
Systemic
mycosis
Trichophyton
concentriucum
Trichophyton
rubrum
Disease
Affected area
Sporotichosis
Skin, primarily hands,
arms, and legs
Cutaneous
mycosis
Tinea imbricate
Smooth body skin
Cutaneous
mycosis
Tinea manuum
Palms and fingers
Tinea pedis
Feet, interdigital
spaces, and soles
Tinea unguium
Nails
Tinea cruris
Groin
T. mentagrophyte
Trichophyton spp.
Tinea corporis
Smooth body skin
Cutaneous
mycosis
Tinea favosa
Scalp, skin, and nails
Trichophyton
spp.
Cutaneous
mycosis
Dermatomycoses
Keratinized layers of
body: skin, hair, nails
Trichophyton
tonsurans
Cutaneous
mycosis
Tinea capitis
Scalp
Cutaneous
mycosis
Tinea barbae
Beard and coarse
body hair
Trichosporon
beigelii
Superficial
mycosis
White piedra
Beard, scalp,
pubic hair
Wangiella
(Phialophora)
dermatitidis
Opportunistic
Systemic
mycosis
Cerebral
Brain or central nervous
chromomycosis
system
Subcutaneous
mycosis
Chromomycosis
Trichophyton
schoenleinii
Trichophyton spp.
Trichophyton spp.
Trichophyton
verrucosum
T. mentagrophytes
Trichophyton spp.
Skin surface, mostly
lower extremities
Maduromycetoma
Wangiella
mansonii
Superficial
mycosis
Tinea nigera
Thick stratum corneum,
palms, and feet
Compiled from Campbell and Stewart (1980); Henry (1984); Howard (2003); Rippon (1988).
49
50
LI AND YANG
fungi (Benenson, 1990; Burge 1990a; Larsen and Frisvad, 1995).
These fungi can cause aspergillosis. In a hospital where an epidemic
of aspergillosis occurred, the source of Aspergillus spores was attributed to a defective disposal conduit door and the dispersal of a
contaminated aerosol from the ward vacuum cleaner, which had the
highest measured concentrations of Aspergillus fumigatus in or around
the building (65 colony forming units/m3 as compared with 0–6 cfu/m3
elsewhere). No further cases were identified in the hospital in
the 2 years after relevant hygiene arrangements were incorporated
(Anderson et al., 1996).
Other clinically important fungal infections include candidiasis
with local mucocutaneous or disseminated systemic organ manifestations and skin mycoses such as dermatophytoses, keratomycosis, tinea
nigra, piedra, and malassezia-caused dermatitis. Invasive fungal diseases of the paranasal sinuses may also be associated with allergic
sinusitis in atopic patients (Fatterpekar, 1999). Aspergillus species
are frequently involved. Noninvasive forms may colonize body cavities
and may be asymptomatic as long as some degree of immunological
resistance can be maintained. Cryptococcus neoformans var. neoformans was isolated from 20 (13%) dwellings out of 154 dwellings in the
metropolitan area of Rio de Janeiro, Brazil, comprising 5 (15.6%) of 32
dwellings of patients with AIDS-associated cryptococcosis (Passoni
et al., 1998).
Histoplasmosis is an intracellular mycotic infection of the reticuloendothelial system caused by the inhalation of conidia from the fungus
Histoplasma capsulatum (Howard, 2003). Histoplasma capsulatum has
a worldwide distribution, but the Mississippi–Ohio River Valley in the
United States is a major endemic region, and the spore is occasionally
found in certain indoor environments there (Collier et al., 1998).
Coccidioides immitis causes coccidioiomycosis, a highly infectious
upper respiratory disease, and infection is caused by inhalation of its
airborne arthrospores (Howard, 2003). The disease is endemic in certain regions, mainly in desert soils and also in the air of endemic areas
in North America (Cox and Wathes, 1995). Exposure to dustborne
spores outdoors is the major risk factor of infection (Al-Doory and
Ramsey, 1987).
C. MYCOTOXINS AND THEIR SIGNIFICANCE TO HUMAN HEALTH
Another public health concern is mycotoxins produced by some
indoor fungi (Table IV). Fungi are capable of producing a number of
secondary metabolites (Nielsen, 2002). Most of these secondary
FUNGAL CONTAMINATION AS A MAJOR CONTRIBUTOR
51
TABLE IV
COMMON MYCOTOXIGENIC INDOOR FUNGI
Fungus
Alternaria alternata
Mycotoxins*
Tenuazonic acid, alternatiol, alternatiol mononethyl ether,
altertoxins
Aspergillus flavus
Aflatoxin B1
Aspergillus fumigatus
Gliotoxin, verrucologen, fumitremorgceusins, fumitoxins,
tryptoquivalins
Aspergillus niger
Naphthopyrone, malformins, nigragillin, orlandin
Aspergillus
ochrrachceus
Ochratoxin A (a carcinogenic kidney toxin)
Aspergillus parasiticus
Aflatoxin B1
Aspergillus versicolar
Sterigmatocystin and methoxysterigmatocystin
Aspergillus ustus
Austaminde, austdiol, austins, austocystins, kotanins X and Y
Chaetomium globosum
Chaetoglobosins, chetomin
Cladosporium
cladosporioides
Cladosporin, emodin
Emericella (Aspergillus) Sterigmatocystin, nudulotoxin
nidulans
Fusarium culmorum
T-2 toxin (immunosuppressive)
Fusarium graminearum Zealralenone
Fusarium verticillioides Fumonisins
(¼ F. moniliforme)
Memnoniella
echinata
Trichodermol, trichodermin, dechlorogrisseofulvins,
memnobotrins A and B, memenoconol, memnoconone
Paecilomyces variotii
Patulin, viriditoxin
Penicillium
aurantiogriseum
Auranthine, penicillic acid, verrucosidin,
nephrotoxic glycopeptides
Mycophenolic acid
Penicillium
brevcompactum
Penicillium
chrysogenum
Roquefortine C, meleagrin, chrysogin, penicillin
Penicillium expansum
Citrinin, patulin (nephrotoxic), cytotoxic metabolite
of unknown origin
Penicillium polonicum
3-methoxyviridicatin, verrucosidin, verrucofortine
Penicillium verrucosum Ochratoxin A (a carcinogenic kidney toxin)
Stachybotrys chartarum Macrocyclic trichothecenes: satratoxins, verrucarins,
(syn ¼ S. atra).
roridins, atranones, dolabellanes, stachybotrylactones,
and lactams
Trichoderma harzianum Alamethicins, emodin, suzukacillin, trichodermin
Wallemia sebi
Walleminols A and B, walleminone
*Toxins in boldface are of high potency. Compiled in part from Al-Doory and Domson, 1984; Frank
et al., 1999; Macher et al., 1999; Samson, 2000; St-Germain and Summerbell, 1996.
52
LI AND YANG
metabolites are mainly to enhance the fitness of the fungi in nature.
However, when some of these chemical compounds cause detrimental
or toxic response in higher vertebrates at low concentrations, they are
referred to as mycotoxins (Nielsen, 2002). Mycotoxicosis is defined as
the disease resulting from exposure to a mycotoxin (CAST, 2003).
Mycotoxicosis may be acute or chronic. More occult disease may
occur when the mycotoxin interferes with the immune system and
leads to a compromised immune system so as to make patients more
susceptible to infectious diseases. Major mycotoxicoses include aflatoxicosis, ochratoxicosis, trichothecene toxicoses, citreviridin toxicosis, zearalenone toxicosis, fumonisin toxicosis, gliotoxin toxicosis, and
immunomodulation.
Mycotoxins’ detrimental effects on human health are at work
when they are ingested (CAST, 2003; Matossian, 1989), inhaled
(CAST, 2003; Croft et al., 1986; Johanning et al., 1993; Miller, 1993;
Smoragiewicz et al., 1993), or absorbed through skin contact (CAST,
2003; Dill et al., 1997; Singh, 1994). Historically, human exposure to
mycotoxins is mainly through ingestion of foodstuff containing or
contaminated with mycotoxins (CAST, 2003). However, because of
increases in public awareness of the health effects of indoor fungi,
inhalation of mycotoxin-containing spores of indoor fungi has become
a major public health concern in the indoor environment, and ingestion and dermal contact play a secondary role in indoor exposure.
There are reportedly more than 200 mycotoxins produced by various
common fungi, per the World Health Organization (WHO) Environmental Health Criterion 105 on mycotoxins (Yang et al., 2002). Samson
(1992) and Smoragiewicz et al. (1993) suggested that there are more
than 400 toxic metabolites at present. The actual number of mycotoxins
is not known, but the number of fungal toxic metabolites could be
potentially in the thousands (CAST, 2003). With molecular masses
between 200 and 800 kDa (Smoragiewicz et al. 1993), mycotoxins are
not volatile at ambient temperatures (Tuomi et al. 2000). Schiefer
(1990) considered that mycotoxins generally have low volatility, and
therefore inhalation of volatile mycotoxins is not very likely. A task
group of WHO concluded that an association between trichothecene
exposure and human disease episodes is possible; however, only
limited data are available (Yang et al., 2002).
Major genera of toxigenic fungi include Aspergillus, Penicillium,
Fusarium, Stachybotrys, Memnoniella, and Claviceps (CAST, 2003).
There are other genera of mycotoxin-producing fungi. Species of 46
fungal genera have been reported to produce mycotoxins (Kendrick,
2000). Major classes of mycotoxins include aflatoxins, trichothecenes,
FUNGAL CONTAMINATION AS A MAJOR CONTRIBUTOR
53
fumonisins, zearalenone, ochratoxin A, and ergot alkaloids
(CAST, 2003). Major toxigenic fungi and the mycotoxins produced,
as well as their health effects, are compiled in Tables V and VI. It
should be pointed out that some of the fungi in Table V are often found
indoors.
Mycotoxins are an integral part of the fungal spores or in association
with dust particles when released into the substrates. Water-damaged
building materials are often contaminated with fungi that produce
detectable levels of mycotoxins (Nikulin, 1999), which may be aerosolized and contribute to pollution in indoor air. Sorenson et al. (1987)
showed that aerosolized conidia of S. chartarum (syn. S. atra)
TABLE V
FUNGI IMPLICATING SOME HUMAN DISEASES BECAUSE OF INVOLVEMENT OF THEIR MYCOTOXINS
Etiologic agent
Disease
Natural substrate
Fusarium spp.
Akakabio-byo
Wheat, barley, oats, rice
Fusarium spp.
Alimentary toxic aleukia
(ATA or septic angina)
Cereal grains (toxic bread)
Penicillium
Balkan nephropathy
Cereal grains
Aspergillus spp.,
Penicillium spp.
Cardiac beriberi
Rice
Sclerotinia
Celery harvester’s
disease
Celery (pink rot)
Dendrodochium
toxicum
Dendrodochiotoxicosis
Fodder (skin contact, inhaled
fodder particles)
Claviceps
purpurea
Ergotism
Rye, cereal grains
Fusarium
moniliforme
Esophageal tumors
Corn
Apergillus flavus,
A. parasiticus
Hepatocarcinoma
(acute aflatoxicosis)
Cereal grains, peanuts
Fusarium
Kashin Beck disease,
‘‘Urov disease’’
Cereal grains
Aspergillus flavus,
A. parasiticus
Kwashiorkor
Cereal grains
Phoma sorghina
Onyalai
Millet
Aspergillus
Reye’s syndrome
Cereal grains
Satchybotrys
chartarum
Stachybotryotoxicosis
Hay, cereal grains, fodder (skin
contact, inhaled haydust)
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TABLE VI
MYCOTOXINS AND THEIR PATHOLOGICAL EFFECTS ON HUMANS AND ANIMALS
Mycotoxin
Aflatoxins
(B1, B2, G1,
G2, M1, M2)
Substrates
Peanuts, corn,
wheat, rice,
cottonseed,
copra, nuts,
various foods,
milk, eggs,
cheese, figs
Affected species
Pathological effects
Hepatotoxicity
Birds
(liver damage)
Duckling,
Bile duct hyperplasia
turkey, poultry,
pheasant chick, Hemorrhage
Intestinal tract
mature chicken,
Kidneys
quail
Carcinogenesis
Mammals
(liver tumors)
Young pigs,
pregnant sows,
dog, calf,
mature cattle,
sheep, cat,
monkey, human
Fish
Laboratory
animals
Citrinin
Cereal grains
(wheat, barley,
corn, rice)
Swine, dog,
laboratory
animals
Nephrotoxicity (tubular
necrosis of kidney)
porcine nephropathy
Cyclopiazonic
acid
Corn, peanuts,
cheese,
kodo millet
Chicken, turkey,
swine, rat,
guinea pig,
human
Muscle necrosis
Intestinal hemorrhage
and edema
Oral lesions
Ochratoxin A
Swine, dog,
Cereal grains,
duckling,
(wheat, barley,
chicken, rat,
oats, corn), dry
human
beans, moldy
peanuts, cheese,
grapes, dried
fruits, wine
Patulin
Moldy feed,
rotted apples,
apple juice,
wheat straw
residue
Birds
Chicken,
chicken embryo,
quail
Mammals
Cat, cattle,
mouse, rabbit,
rat, human
Nephrotoxicity (tubular
necrosis of kidney)
Porcine nephropathy
Mild liver damage
Enteritis
Teratogenesis
Carcinogenesis
(kidney tumors)
Urinary tract tumors
Edema
Brain
Lungs
Hemorrhage
Lungs
Capillary damage
Liver
(continued)
FUNGAL CONTAMINATION AS A MAJOR CONTRIBUTOR
55
TABLE VI (Continued )
Mycotoxin
Substrates
Affected species
Others
Brine shrimp,
guppie, zebra
Fish larvae
Pathological effects
Spleen
Kidney
Paralysis of
motor nerves
Convulsions
Carcinogenesis
Antibiotic
Mouse, rat,
Liver damage (fatty liver,
chicken embryo, cell necrosis); kidney
quail, brine
damage; digitalis-like
shrimp
action on heart dilates
blood vessels;
antidiuretic edema in
rabbit skin;
carcinogenesis;
antibiotic
Penicillic
acid
Stored corn,
cereal grains,
dried beans,
moldy tobacco
Penitrem
Moldy cream
Dog, mouse,
cheese, English
human
walnuts,
hamburger
bun, beer
Tremors, death,
icoordination, bloody
diarrhea
Sterigmatocystin
Green coffee,
Mouse, rat
moldy wheat,
grains,
hard cheeses,
peas, cottonseed
Carcinogenesis
Hepatotoxin
Corn, wheat,
Trichothecenes
commercial
(T-2 toxin,
diacetoxyscirpenol, cattle feed,
mixed feed,
neosolaniol,
barley, oats
nivalenol,
diacetylnivalenol,
deoxynicalenol,
HT-2 toxin,
fusarenon X)
Zearalenone
Digestive disorders
Swine, cattle,
(emesis, diarrhea,
chicken, turkey,
refusal to eat),
horse, rat, dog,
hemorrhage (stomach,
mouse, cat,
heart, intestines, lungs,
human
bladder, kidney), edema,
oral lesions, dermatitis,
blood disorders
(leucopenia)
Estrogenic effects
Corn, moldy hay, Swine, dairy
(edema of vulva,
pelleted comcattle, chicken,
prolapse of vagina,
mercial feed
turkey, lamb,
enlargement of uterus)
rat, mouse,
guinea pig
Atrophy of testicles
Atrophy of ovaries,
enlargement of
mammary glands
Abortion
Compiled from CAST (2003).
56
LI AND YANG
contained trichothecene mycotoxins in the laboratory. The most common toxin was satratoxin H. Lesser amounts of satratoxin G and trichoverrols A and B were also detected, but less frequently. They also found
that most of the airborne particles were within respirable range. Similar
experiments, conducted by Pasanen et al. (1993), demonstrated that
trichothecene mycotoxins were in airborne fungal propagules of S.
chartarum (S. atra) and could be collected on membrane filters. Conidia of A. flavus and A. parasiticus were reported to contain aflatoxins
(Wicklow and Shotwell, 1983). Miller (1993) also reported detection of
two mycotoxins, deoxynivalenol and T-2 toxin, in conidia of Fusarium
graminearum and F. sporotrichioides, respectively. These references
suggest that inhalation exposure to conidia may also increase the
chance of exposure to mycotoxins.
Studies indicated that some secondary metabolites of indoor airborne fungi could be responsible for health problems of occupants
(Croft et al. 1986; Pieckova, 2002). Croft et al. (1986) identified several
cases of mycotoxicoses caused by airborne exposure to the toxigenic
fungus S. chartarum (syn. S. atra) in a residential building. Spengler
et al. (1993) reported that a higher rate of upper respiratory tract and
lung cancer occurred among workers with a high risk of inhalation of
fungi in the grain and food handling industry.
Important indoor toxigenic fungi include Stachybotrys chartarum
(syn. S. atra), Memnoniella echinata, Aspergillus species, Penicillium
species, Fusarium species, Trichoderma species, and Paecilomyces
species. These fungi are well documented to have associations with
detrimental health effects in humans and animals by ingestion. However, many toxigenic fungi—such as Stachybotrys chartarum and species of Aspergillus, Penicillium, and Fusarium—have been found to
infest buildings with known indoor air problems and sick building
syndrome (Croft et al., 1986; Flannigan et al., 1991; Johanning et al.,
1993).
It should be pointed out that most mycotoxin studies were conducted on post-harvest stored or processed food. For better indoor
environmental quality evaluation, it is important to know whether
indoor fungi are able to produce mycotoxin in building materials or
not and under what conditions. Tuomi et al. (2000) analyzed 17 mycotoxins from 79 bulk building materials collected from water-damaged
buildings. Their results showed sterigmatocystin was present in 24%
of the samples, trichothecenes in 19% of the samples, and citrinine in 3
samples. Aspergillus versicolor was found on most sterigmatocysincontaining samples, and Stachybotrys spp. were found on the samples
in which satratoxins were present (Tuomi et al., 2000).
FUNGAL CONTAMINATION AS A MAJOR CONTRIBUTOR
57
Nielsen (2002) showed that Stachybotrys chartarum produced a
number of mycotoxins on building materials at levels significantly
higher than these products by other fungi. More importantly, he discovered that only 35% of the isolates of S. chartarum produced the
extremely cytotoxic satratoxins. He opined that satratoxins might not
be responsible for idiopathic pulmonary hemosiderosis (IDPH) in infants and that this disease may be caused by other mycotoxins produced by S. chartarum (Nielsen, 2002). Similar results showed that
39% of S. chartarum produced macrocyclic trichothecenes (Andersen
et al., 2002). The toxicity of the isolates producing macrocyclic trichothecenes is 1000 times that of other isolates, which produce atronones (Jarvis 2003, per. com.). However, a recent study in Belgium
showed that in 6 IDPH cases, the isolates of S. chartarum recovered
from patients’ homes were all atronones producers (Nielsen, per. com.).
This association further raised the question whether other mycotoxins
and secondary metabolites are responsible for IDPH. To answer this
question there is no doubt that more research is necessary.
Aflatoxins are toxins discovered in 1961 from Aspergillus flavus and
A. parasiticus and considered human and animal carcinogens (CAST,
2003; International Agency for Research on Cancer, 1993). Aflatoxins
are potent liver toxins. A sublethal dose from exposure may result in
cancer (CAST, 2003). Aflatoxin-induced disease has been well documented and reviewed (Henry and Cole, 1993; International Agency for
Research on Cancer, 1993; Kurup, 1999). Aspergillus versicolor produced the mycotoxins sterigmatocystin and 5-methoxysterigmatocystin, which are precursors of aflatoxins, in water-damaged materials
under field conditions and experimental conditions (Gravesen et al.,
1999; Nielsen, 2002). Trichothecene toxins inhibit protein and DNA
synthesis (CAST, 2003). The data of health effects on animals are
‘‘inadequate evidence’’ for humans (International Agency for Research
on Cancer, 1993). Macrocyclic trichothe